tbuckley/cabot-search huggingface dataset:
Increased cell senescence in human metabolic disorders
Authors: Rosa Spinelli, Ritesh Kumar Baboota, Silvia Gogg, Francesco Beguinot, Matthias Blüher, Annika Nerstedt, Ulf Smith
Journal: Journal of Clinical Investigation (2023)

Cell senescence (CS) is at the nexus between aging and associated chronic disorders, and aging increases the burden of CS in all major metabolic tissues. However, CS is also increased in adult obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease independent of aging. Senescent tissues are characterized by dysfunctional cells and increased inflammation, and both progenitor cells and mature, fully differentiated and nonproliferating cells are afflicted. Recent studies have shown that hyperinsulinemia and associated insulin resistance (IR) promote CS in both human adipose and liver cells. Similarly, increased CS promotes cellular IR, showing their interdependence. Furthermore, the increased adipose CS in T2D is independent of age, BMI, and degree of hyperinsulinemia, suggesting premature aging. These results suggest that senomorphic/senolytic therapy may become important for treating these common metabolic disorders.
Major trauma presentations and patient outcomes in English hospitals during the COVID-19 pandemic: An observational cohort study
Authors: Carl Marincowitz, Omar Bouamra, Tim Coats, Dhushy Surendra Kumar, David Lockey, Lyndon Mason, Virginia Newcombe, Julian Thompson, Antoinette Edwards, Fiona Lecky
Journal: PLoS Medicine (2023)

Background Single-centre studies suggest that successive Coronavirus Disease 2019 (COVID-19)-related “lockdown” restrictions in England may have led to significant changes in the characteristics of major trauma patients. There is also evidence from other countries that diversion of intensive care capacity and other healthcare resources to treating patients with COVID-19 may have impacted on outcomes for major trauma patients. We aimed to assess the impact of the COVID-19 pandemic on the number, characteristics, care pathways, and outcomes of major trauma patients presenting to hospitals in England. Methods and findings We completed an observational cohort study and interrupted time series analysis including all patients eligible for inclusion in England in the national clinical audit for major trauma presenting between 1 January 2017 and 31 of August 2021 (354,202 patients). Demographic characteristics (age, sex, physiology, and injury severity) and clinical pathways of major trauma patients in the first lockdown (17,510 patients) and second lockdown (38,262 patients) were compared to pre-COVID-19 periods in 2018 to 2019 (comparator period 1: 22,243 patients; comparator period 2: 18,099 patients). Discontinuities in trends for weekly estimated excess survival rate were estimated when lockdown measures were introduced using segmented linear regression. The first lockdown had a larger associated reduction in numbers of major trauma patients (−4,733 (21%)) compared to the pre-COVID period than the second lockdown (−2,754 (6.7%)). The largest reductions observed were in numbers of people injured in road traffic collisions excepting cyclists where numbers increased. During the second lockdown, there were increases in the numbers of people injured aged 65 and over (665 (3%)) and 85 and over (828 (9.3%)). In the second week of March 2020, there was a reduction in level of major trauma excess survival rate (−1.71%; 95% CI: −2.76% to −0.66%) associated with the first lockdown. This was followed by a weekly trend of improving survival until the lifting of restrictions in July 2020 (0.25; 95% CI: 0.14 to 0.35). Limitations include eligibility criteria for inclusion to the audit and COVID status of patients not being recorded. Conclusions This national evaluation of the impact of COVID on major trauma presentations to English hospitals has observed important public health findings: The large reduction in overall numbers injured has been primarily driven by reductions in road traffic collisions, while numbers of older people injured at home increased over the second lockdown. Future research is needed to better understand the initial reduction in likelihood of survival after major trauma observed with the implementation of the first lockdown.
An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity
Authors: Kathryn L. Roche, Stacy Remiszewski, Matthew J. Todd, John L. Kulp, Liudi Tang, Alison V. Welsh, Ashley P. Barry, Chandrav De, William W. Reiley, Angela Wahl, J. Victor Garcia, Micah A. Luftig, Thomas Shenk, James R. Tonra, Eain A. Murphy, Lillian W. Chiang
Journal: Journal of Clinical Investigation (2023)

Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.
Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation
Authors: Enrique M. Ocio, Aurore Perrot, Pierre Bories, Jesus F. San-Miguel, Igor W. Blau, Lionel Karlin, Joaquin Martinez-Lopez, Song-Yau Wang, Sara Bringhen, Magda Marcatti, María-Victoria Mateos, Paula Rodriguez-Otero, Stefania Oliva, Axel Nogai, Nadia Le Roux, Liyan Dong, Sandrine Macé, Matthieu Gassiot, Thomas Fitzmaurice, Corina Oprea, Philippe Moreau
Journal: Leukemia (2023)

Abstract Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population ( n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10 −5 sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).
Tubular Elabela-APJ axis attenuates ischemia-reperfusion induced acute kidney injury and the following AKI-CKD transition by protecting renal microcirculation
Authors: Mingrui Xiong, Hong Chen, Yu Fan, Muchuan Jin, Dong Yang, Yuchen Chen, Yu Zhang, Robert B Petersen, Hua Su, Anlin Peng, Congyi Wang, Ling Zheng, Kun Huang
Journal: Theranostics (2023)

Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear.
Complement C3aR depletion reverses HIF-1α–induced metabolic impairment and enhances microglial response to Aβ pathology
Authors: Manasee Gedam, Michele M. Comerota, Nicholas E. Propson, Tao Chen, Feng Jin, Meng C. Wang, Hui Zheng
Journal: Journal of Clinical Investigation (2023)

Microglia are the major cell type expressing complement C3a receptor (C3aR) in the brain. Using a knockin mouse line in which a Td-tomato reporter is incorporated into the endogenous C3ar1 locus, we identified 2 major subpopulations of microglia with differential C3aR expression. Expressing the Td-tomato reporter on the APPNL-G-F-knockin (APP-KI) background revealed a significant shift of microglia to a high-C3aR-expressing subpopulation and they were enriched around amyloid β (Aβ) plaques. Transcriptomic analysis of C3aR-positive microglia documented dysfunctional metabolic signatures, including upregulation of hypoxia-inducible factor 1 (HIF-1) signaling and abnormal lipid metabolism in APP-KI mice compared with wild-type controls. Using primary microglial cultures, we found that C3ar1-null microglia had lower HIF-1α expression and were resistant to hypoxia mimetic-induced metabolic changes and lipid droplet accumulation. These were associated with improved receptor recycling and Aβ phagocytosis. Crossing C3ar1-knockout mice with the APP-KI mice showed that C3aR ablation rescued the dysregulated lipid profiles and improved microglial phagocytic and clustering abilities. These were associated with ameliorated Aβ pathology and restored synaptic and cognitive function. Our studies identify a heightened C3aR/HIF-1α signaling axis that influences microglial metabolic and lipid homeostasis in Alzheimer disease, suggesting that targeting this pathway may offer therapeutic benefit.
Mechanisms for regulation of RAS palmitoylation and plasma membrane trafficking in hematopoietic malignancies
Authors: Fang Yu, Zhijian Qian
Journal: Journal of Clinical Investigation (2023)

Palmitoylation is a critical posttranslational modification that enables the cellular membrane localization and subsequent activation of RAS proteins, including HRAS, KRAS, and NRAS. However, the molecular mechanism that regulates RAS palmitoylation in malignant diseases remains unclear. In this issue of the JCI, Ren, Xing, and authors shed light on this topic and revealed how upregulation of RAB27B, as a consequence of CBL loss and Janus kinase 2 (JAK2) activation, contributes to leukemogenesis. The authors found that RAB27B mediated NRAS palmitoylation and plasma membrane localization by recruiting ZDHHC9. The findings suggest that targeting RAB27B could provide a promising therapeutic strategy for NRAS-driven cancers.
Negativity begets longevity in T cells
Authors: H. Alex Feldman, Hilal Cevik, Stephen N. Waggoner
Journal: Journal of Clinical Investigation (2023)

Killer immunoglobulin-like receptors (KIRs) are polymorphic receptors for human leukocyte antigens (HLAs) that provide positive or negative signals controlling lymphocyte activation. Expression of inhibitory KIRs by CD8+ T cells affects their survival and function, which is linked to improved antiviral immunity and prevention of autoimmunity. In this issue of the JCI, Zhang, Yan, and co-authors demonstrate that increased numbers of functional inhibitory KIR-HLA pairs equating to greater negative regulation promoted longer lifespans of human T cells. This effect was independent of direct signals provided to KIR-expressing T cells and was instead driven by indirect mechanisms. Since the long-term maintenance of CD8+ T cells is critical for immune readiness against cancer and infection, this discovery has implications for immunotherapy and the preservation of immune function during aging.
High-intensity interval training ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization
Authors: Shu Feng, Chongyun Wu, Peibin Zou, Qianting Deng, Zhe Chen, Meng Li, Ling Zhu, Fanghui Li, Timon Cheng-Yi Liu, Rui Duan, Luodan Yang
Journal: Theranostics (2023)

Background: Alzheimer's disease (AD), one of the most common forms of dementia, is a widely studied neurodegenerative disease characterized by Aβ accumulation and tau hyperphosphorylation. Currently, there is no effective cure available for AD.The astrocyte AQP4 polarized distribution-mediated glymphatic system is essential for Aβ and abnormal tau clearance and is a potential therapeutic target for AD.However, the role of exercise on the AQP4 polarized distribution and the association between the AQP4 polarized distribution and astrocyte phenotype polarization are poorly understood.Methods: Using a streptozotocin (STZ)-induced sporadic AD rat model, we investigated the effects of high-intensity interval training on AD pathologies.The Branes maze task was conducted to measure spatial learning and memory.Immunofluorescence staining of NeuN with TUNEL, Fluoro-Jade C, and relative neuronal damage markers was applied to measure neuronal apoptosis, neurodegeneration, and damage.Sholl analysis was carried out to analyze the morphology of microglia.Line-scan analysis, 3D rendering, and the orthogonal view were applied to analyze the colocalization.Western blot analysis and enzyme-linked immunosorbent assay (ELISA) analysis were conducted to examine AQP4 and Aβ, respectively.An APP/PS1 transgenic AD mice model was used to confirm the key findings.Results: High-intensity interval training (HIIT) alleviates cognitive dysfunction in STZ-induced AD-like rat models and provides neuroprotection against neurodegeneration, neuronal damage, and neuronal loss.Additionally, HIIT improved the drainage of abnormal tau and Aβ from the cortex and hippocampus via the glymphatic system to the kidney.Further mechanistic studies support that the beneficial effects of HIIT on AD might be due, in part, to the polarization of glial cells from a neurotoxic phenotype towards a neuroprotective phenotype.Furthermore, an intriguing finding of our study is that the polarized distribution of AQP4 was strongly correlated with astrocyte phenotype.We found A2 phenotype exhibited more evident AQP4 polarization than the A1 phenotype. Conclusion:Our findings indicate that HIIT ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype and astrocyte phenotype-associated AQP4 polarization.These changes promote Aβ and p-tau clearance from the brain tissue through the glymphatic system and the kidney.
Microtubule stabilization targeting regenerative chondrocyte cluster for cartilage regeneration
Authors: Jiawei Li, Chunmei Fan, Zhongyang Lv, Ziying Sun, Jie Han, Maochun Wang, Huiming Jiang, Kuoyang Sun, Guihua Tan, Hu Guo, Anlong Liu, Heng Sun, Xingquan Xu, Rui Wu, Wenjin Yan, Qing Jiang, Shiro Ikegawa, Xiao Chen, Dongquan Shi
Journal: Theranostics (2023)

Purpose: Chondrocytes (CHs) in cartilage undergo several detrimental events during the development of osteoarthritis (OA).However, the mechanism underlying CHs regeneration involved in pathogenesis is largely unknown.The aim of this study was to explore the underlying mechanism of regeneration of CHs involved in the pathological condition and the potential therapeutic strategies of cartilage repair.Methods and Materials: CHs were isolated from human cartilage in different OA stages and the high-resolution cellular architecture of human osteoarthritis was examined by applying single-cell RNA sequencing.The analysis of gene differential expression and gene set enrichment was utilized to reveal the relationship of cartilage regeneration and microtubule stabilization.Microtubule destabilizer (nocodazole) and microtubule stabilizer (docetaxel) treated-human primary CHs and rats cartilage defect model were used to investing the effects and downstream signaling pathway of microtubule stabilization on cartilage regeneration.Results: CHs subpopulations were identified on the basis of their gene markers and the data indicated an imbalance caused by an increase in the degeneration and disruption of CHs regeneration in OA samples.Interestingly, the CHs subpopulation namely CHI3L1 + CHs, was characterized by the cell regenerative capacity, stem cell potency and the activated microtubule (MT) process.Furthermore, the data indicated that MT stabilization was effective in promoting cartilage regeneration in rats with cartilage injury model by inhibiting YAP activity.Conclusion: These findings lead to a new understanding of CHs regeneration in the OA pathophysiology context and suggest that MT stabilization is a promising therapeutic target for OA and cartilage injury.
Connective Tissue Disease-Associated Interstitial Lung Disease
Authors: Reeba Mathew, Sungryong Noh
Journal: Thorax (2023)

Various systemic autoimmune connective tissue disorders are associated with interstitial lung disease (ILD). Rheumatoid arthritis involves the joints; thoracic manifestations include ILD, diseases of the pleura, small or large airways, and pulmonary arteries. Systemic lupus erythematosus (SLE) is a relapsing–remitting chronic autoimmune disease that can affect multiple organs. Pulmonary involvement is more commonly seen in SLE than in any other connective tissue diseases. Sjogren syndrome occurs due to inflammatory lymphocytic infiltration of glandular and extraglandular organs. It is characterized by diminished function of exocrine glands that lead to eye and mouth dryness (sicca syndrome). ILD and small airway disease are the most common forms of lung involvement in Sjogren. Systemic sclerosis is a connective tissue disorder with multisystem involvement characterized by dysregulation of the immune system, and excess collagen formation leading to fibrosis of skin, vascular system, and multiple organs. ILD is more likely to develop in diffuse cutaneous systemic sclerosis than in the limited cutaneous entity. Dermatomyositis (DM) and polymyositis (PM) belong to a group of idiopathic inflammatory myopathies, which are connective tissue disorders that mostly involve the skeletal muscle. ILD is the major determinant of mortality and morbidity in patients with DM and PM. Ankylosing spondylitis (AS) is a chronic progressive autoimmune disorder involving the spine, the sacroiliac joints, and less commonly the peripheral joints. Pulmonary apical fibrosis is one of the commonest pulmonary features seen in AS. Relapsing polychondritis (RP) is a rare relapsing–remitting autoimmune disorder that causes inflammation predominantly of cartilaginous tissues. Airway involvement in the form of sub-glottic stenosis, tracheobronchomalacia, thickened and calcified tracheal wall with sparing of the posterior membranous wall, and tracheal stenosis which can be localized or diffuse are frequently seen pulmonary features in RP. Finally, mixed connective tissue disease comprises combination or overlap of systemic sclerosis, SLE, and DM/PM.
Loss of STAT2 may be dangerous in a world filled with viruses
Authors: Michael B. Jordan
Journal: Journal of Clinical Investigation (2023)

Type I IFNs, a family of cytokines that signal through a single receptor and signaling mechanism, were originally named for their ability to interfere with viral replication. While type II IFN (IFN-γ) largely protects against intracellular bacteria and protozoa, type I IFNs largely protect from viral infections. Inborn errors of immunity in humans have demonstrated this point and its clinical relevance with increasing clarity. In this issue of the JCI, Bucciol, Moens, et al. report the largest series of patients to date with deficiency of STAT2, an important protein for type I IFN signaling. Individuals with STAT2 loss demonstrated a clinical phenotype of viral susceptibility and inflammatory complications, many of which remain poorly understood. These findings further illustrate the very specific and critical role that type I IFNs play in host defense against viruses.
Lactoferrin attenuates cardiac fibrosis and cardiac remodeling after myocardial infarction via inhibiting mTORC1/S6K signaling pathway
Authors: Tianbao Ye, Zhiwen Yan, Cheng Chen, Di Wang, Aiting Wang, Taixi Li, Boshen Yang, Xianting Ding, Chengxing Shen
Journal: Theranostics (2023)

Rationale: Myocardial infarction (MI) causes a severe injury response that eventually leads to adverse cardiac remodeling and heart failure.Lactoferrin (Ltf), as a secreted protein, bears multi-pharmacological properties.Present study aims to establish the cardioprotective function and corresponding mechanism of Ltf in MI process. Methods and results:We performed proteomic analysis in Tregs derived from MI heart, and identified Ltf as a remarkably upregulated secreted protein.However, Ltf was decreased in circulation and positively correlated with cardiac function both in mice and patients after MI.Ltf administration remarkably alleviated cardiac fibrosis and remodeling, improved cardiac function, and reduced incidence of heart failure in mice post-MI.In vitro, Ltf suppressed fibroblast to myofibroblast conversion induced by transforming growth factor-β (TGF-β).Mechanistically, phosphoproteomic landscape analysis revealed that Ltf repressed the activation of mTORC1/S6K/eIF-4B signaling pathway via interaction with CD74 receptor.Administration of mTORC1/S6K/eIF-4B axis agonist MHY1485 abolished the cardioprotective effects of Ltf.Besides, MHY1485 also markedly reversed the effects of Ltf on suppressing the transformation of fibroblast to myofibroblast mediated by TGF-β. Conclusion:Our study established the cardiac protective role of Ltf in attenuating cardiac remodeling and improving cardiac function by inhibiting the activation of myofibroblasts through suppressing mTORC1/S6K/eIF-4B signaling pathway post-MI.Treatment with Ltf may serve as a potential novel therapeutic intervention in patients with MI.
Diagnosis of acute myocardial infarction using a combination of circulating circular RNA cZNF292 and clinical information based on machine learning
Authors: Qiulian Zhou, Jes‐Niels Boeckel, Jianhua Yao, Juan Zhao, Yuzheng Bai, Yicheng Lv, Meiyu Hu, Danni Meng, Yuan Xie, Pujiao Yu, Peng Xi, Jiahong Xu, Yi Zhang, Stefanie Dimmeler, Junjie Xiao
Journal: MedComm (2023)

Circulating circular RNAs (circRNAs) are emerging as novel biomarkers for cardiovascular diseases (CVDs). Machine learning can provide optimal predictions on the diagnosis of diseases. Here we performed a proof-of-concept study to determine if combining circRNAs with an artificial intelligence approach works in diagnosing CVD. We used acute myocardial infarction (AMI) as a model setup to prove the claim. We determined the expression level of five hypoxia-induced circRNAs, including cZNF292, cAFF1, cDENND4C, cTHSD1, and cSRSF4, in the whole blood of coronary angiography positive AMI and negative non-AMI patients. Based on feature selection by using lasso with 10-fold cross validation, prediction model by logistic regression, and ROC curve analysis, we found that cZNF292 combined with clinical information (CM), including age, gender, body mass index, heart rate, and diastolic blood pressure, can predict AMI effectively. In a validation cohort, CM + cZNF292 can separate AMI and non-AMI patients, unstable angina and AMI patients, acute coronary syndromes (ACS), and non-ACS patients. RNA stability study demonstrated that cZNF292 was stable. Knockdown of cZNF292 in endothelial cells or cardiomyocytes showed anti-apoptosis effects in oxygen glucose deprivation/reoxygenation. Thus, we identify circulating cZNF292 as a potential biomarker for AMI and construct a prediction model "CM + cZNF292."